EP2520580B1 - Halogenated dideoxy saccharide derivatives, preparation method and use thereof - Google Patents

Halogenated dideoxy saccharide derivatives, preparation method and use thereof Download PDF

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Publication number
EP2520580B1
EP2520580B1 EP10840284.3A EP10840284A EP2520580B1 EP 2520580 B1 EP2520580 B1 EP 2520580B1 EP 10840284 A EP10840284 A EP 10840284A EP 2520580 B1 EP2520580 B1 EP 2520580B1
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EP
European Patent Office
Prior art keywords
compound
strong
cancer
reaction
dichloromethane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP10840284.3A
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German (de)
English (en)
French (fr)
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EP2520580A1 (en
EP2520580A4 (en
Inventor
Hua Mao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SUZHOU HARMONY BIOTECHNOLOGY CO Ltd
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SUZHOU HARMONY BIOTECHNOLOGY CO Ltd
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C07H11/04—Phosphates; Phosphites; Polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen

Definitions

  • the current invention is related to pharmaceutical chemistry, and in particular a method to produce halogenated dideoxy sugar derivates as well as their applications.
  • sugars can boost immune system, and have anti-bacteria and anti-tumor effects.
  • One kind of sugars is named as 2-deoxy-glucose, whose structural characteristic is that the -OH on 2 position of the sugar ring is replaced by H, alkyl, amino group and other functional groups. This kind of sugar has anti-tumor effect.
  • George Tidmarsch et al has applied for a patent named "Treatment of cancer with 2-deoxyglucose" ( U.S. patent number: 6979675 ) based on the anti-tumor effect of 2-DG (2-deoxygluclose).
  • the inventor of the current invention has discovered that, when acetylated and halogenated, deoxy sugars can be more easily absorbed and enter into cancer cells faster.
  • the hydroxyl group on its 1 position is halogenated, the halogenated deoxy sugar formed has a much stronger effect (according to normal tumor cell test), and it is also easier to product derivates.
  • the anti-tumor function of acetylated deoxy sugars can be significantly enhanced.
  • This kind of sugars possess general anti-tumor effects, not only to common cancers, such as stomach cancer, esophagus cancer, liver cancer, bile cancer, rectum cancer, intestinal cancer, lung cancer, rhinopharyngocele, prostate cancer, nervous system cancer, breast cancer, ovarian cancer, cervis cancer, etc., but also to malignant melanoma, pancreas cancer, anaplastic thyroid carcinoma, metastatictumorofbone, leukemia and other malignant cancers.
  • WO 90/04597 A1 discloses a process for preparing glycoconjugates of phosphoramides in which the sugar is linked to the phosphoramide mustard function or the ifosfamide mustard function and the sugar may be present as mono-, di- or polysaccharides in all existing isomeric and enantiomeric forms by conjugating protected bromine sugar in a manner known per se with the corresponding phosphorus compounds and releasing it from the protective groups. Also described are D-glycopyranosyl-N,N'-di(2-chloroethyl)-phosphoric acid diamides and the use of the compounds as antitumoral agents.
  • WO 2008/011588 A2 discloses bromoglufosfamide and related compounds are useful in the treatment of cancer and other hyperproliferative diseases.
  • Glufosfamide and bromoglufosfamide are synthesized by reacting the corresponding tetracetyl derivatives with MeOH and a catalytic amount of MeO(-).
  • Tetraacetyl glulufosfamide is obtained by reacting a tetraacetyl trichloroacetamidate intermediate of glucose, ifosfamide mustard, and an acid in an anhydrous polar solvent.
  • WO 2009/086720 A1 discloses 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl-[N,N'-di-(2-chloroethyl)]-phosphoric acid diamide I, its a-configuration II and its ⁇ -configuration III. These compounds show inhibitory action on transplantation tumors in mouse from the pharmacodynamic test and low toxicity from pharmacological toxicity test. So these compounds can be used for preparation of antitumors drugs.
  • the preparation methods of compounds I, II, III are brief reaction steps, high yields, low cost and suitable for industrialization.
  • the technical problem of the current invention is to overcome the drawbacks present in the current state of the art, and to remedy the structure of deoxy sugar so that it has double anti-tumor effects and a wider treatment scope and can be used to treat malignant melanoma, pancreatic cancer, anaplastic thyroid carcinoma, metastatic tumor of bone, leukemia and other highly malignant carcinomas.
  • the current invention provides a halogenated dideoxy sugar derivative, characterised in that the derivative has the following general structure I wherein X is halogen, or
  • R 1 and R 2 are H or Br; R 3 and R 4 are OH or OAc.
  • the current invention also provides compound c with the following structure. wherein R 1 and R 2 are H or Br respectively; and wherein the compound c comprises compounds 1, 2, 3 and 4 with the following structures: wherein compounds 1, 2, 3 and 4 are all white powders with the following physical characteristics: melting points : compound 1 2 3 4 Melting point (°C) 84 79 88 82 Optical rotation compound 1 2 3 4 Optical rotation° (CHCl3) +5 -26 -23 -50
  • the current invention also provides compound d with the following structure. wherein R 1 and R 2 are H or Br respectively, and wherein the compound d comprises compounds 5, 6, 7 and 8 with the following structures: wherein compounds 5, 6, 7 and 8 are all white powders with the following physical characteristics: melting points : compound 5 6 7 8 Melting point (°C) 120 109 125 113 Optical rotation: compound 5 6 7 8 Optical rotation° (CHCl3) +144 -121 +106 -101
  • the current invention also provides compound e with the following structure: wherein R 1 and R 2 are H or Br respectively, and wherein the compound e comprises compounds 9, 10, 11 and 12 with the following structures: wherein compounds 9, 10, 11 and 12 are all white powders with the following physical characteristics: melting point: compound 9 10 11 12 Melting point (°C) 117 105 118 108 Optical rotation : compound 9 10 11 12 Optical rotation° (CHCl3) +58 -78 -5 -128
  • the current invention also provides compound f with the following structure: wherein R 1 and R 2 are H or Br respectively, and wherein the compound f comprises compounds 13 and 14 with the following structures: wherein compounds 13 and 14 are all white powders with the following physical characteristics: melting points: compound 13 14 Melting point (°C) 107 121 Optical rotation: compound 13 14 Optical rotation° (CHC l3) -85 +57
  • the other object of the current invention is to develop a method to produce the halogenated dideoxy sugar derivative as disclosed above, wherein the reaction mechanisms are as follows:
  • the method comprises the following steps:
  • Another goal of the current invention is to provide a use of halogenated dideoxy sugar derivative as disclosed above in the production of anti-tumor medicament.
  • the current invention discloses the application of compound 1-14 in the treatment of various cancers.
  • Compound 1-14 has strong cytostatic effect on all of the cancer cells above.
  • the inhibition effect of compounds 3, 5, 7, 10, 12 and 14 on mouse transplant tumors Anti-tumor experiments have been conducted on B16 malignant melanoma, AsPc human pancreatic cancer cells, 05-732 human bone tumor, anaplastic thyroid carcinoma TA-K cells, MX-1 human breast cancer cells and MGC human stomach cancer cells. Compound 3, 5, 7, 10, 12 and 14 have significant effect on mouse transplant tumors, especially to malignant melanoma, human pancreatic cancer cells, human bone tumor, anaplastic thyroid carcinoma, human breast cancer cells and human stomach cancer cells.
  • the current invention uses sugar as starting material to synthesize compound 1-14. Since the sugar rings of all the compounds are acetylated hydrophobic esters, they are very easy to be crystallized. The compounds are chemically and enzymetically stable. They are easy to spread after enter the human body and can be absorbed by cancer cells without consuming any energy. Inside cancer cells, they release the anti-cancer elements, dideoxy sugar, mustine, podophyllotoxin with the help of esterase, acylase and glycosidase and the double anti-tumor effect can be achieved.
  • the inventor of the current invention has discovered that after the deoxy sugar is acetylated and brominated, the compound is more ready to be absorbed and the anti-tumor effect thereof is significantly better than deoxy sugar. In addition, when the compound is deacetylated, its anti-tumor effect is also significantly improved. However, it is more difficult to be crystallized and therefore acetylated compound is more preferred.
  • the compound of the current invention can be combined with appropriate excipients and be made into oral medications or non-oral injective agents or external medication. Such as orally administrated pills, capsules, tablets, oral liquids, injections, powder injector, patch or cream.
  • the compounds of the current invention can be used to treat malignant melanoma, pancreas cancer, anaplastic thyroid carcinoma, metastatic tumor of bone, leukemia, lymphoma, osteoma, chondrosarcoma, prostate cancer, esophagus cancer, stomach cancer, liver cancer, bile cancer, rectum cancer, intestinal cancer, colorectal cancer, lung cancer, rhinopharyngocele, nervous system cancer, breast cancer, ovarian cancer, cervis cancer.
  • Example 9 The acute toxicitiy (LD 50) of compound 1-14 (prepared by example 1-8)
  • the results of the acute toxicity and anti-tumor effect of compounds 1-14 are as follows:
  • human colon cancer HT-29 cells, human liver cancer Bel-7402 cells, human rectum cancer cells HCE 8693, human stomach cancer BGC-803 cells, human esophagus cancer CaEs-17 cells, human breast cancer cells MCF-7, human ovarian cancer cells A2780, pancreatic cancer cells PC-3, human bladder cells EJ, human brain glia cells TG-905, human leukemia cells K562, human melanoma M 14 cells and human anaplastic thyroid carcinoma TA-K cells are as follows:
  • the experiment results above show that the compounds 1-14 of the current invention has strong inhibition effect on human nasopharyngeal cancer CNE-2Z cells, human lung cancer A549 cells, human colon cancer HT-29 cells, human liver cancer Bel-7402 cells, human rectum cancer cells HCE 8693, human stomach cancer BGC-803 cells, human esophagus cancer CaEs-17 cells, human breast cancer cells MCF-7, human ovarian cancer cells A2780, pancreatic cancer cells PC-3, human bladder cells EJ, human brain glia cells TG-905, human leukemia cells K562, human melanoma M 14 cells and human anaplastic thyroid carcinoma TA-K cells. They can be used to prepare anti-tumor medicament and have significant clinic value.
  • Compound 3, 5, 7, 10, 12, 14 (the preparation of experiment 2, 3, 4, 5, 6, 8) were applied at a concentration of 125mg/kg. Saline solution was used as a control.
  • the positive group CTX was treated with the compounds at an amount of 0.4ml/20g. The compounds were applied once a day for consecutive 7 days. The animals were then compensated.
  • Anti tumor experiments were carried out on B16 malignant melanoma, AsPc human pancreatic cancer cells, 05-732 human bone tumor, anaplastic thyroid carcinoma TA-K cells, MX-1 human breast cancer cells and MGC human stomach cancer cells respectively.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicinal Preparation (AREA)
EP10840284.3A 2009-12-30 2010-07-26 Halogenated dideoxy saccharide derivatives, preparation method and use thereof Active EP2520580B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200910247577.1A CN102115483B (zh) 2009-12-30 2009-12-30 卤代双去氧糖衍生物及其制备方法与应用
PCT/CN2010/001129 WO2011079494A1 (zh) 2009-12-30 2010-07-26 卤代双去氧糖衍生物及其制备方法与应用

Publications (3)

Publication Number Publication Date
EP2520580A1 EP2520580A1 (en) 2012-11-07
EP2520580A4 EP2520580A4 (en) 2013-09-04
EP2520580B1 true EP2520580B1 (en) 2015-02-25

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EP10840284.3A Active EP2520580B1 (en) 2009-12-30 2010-07-26 Halogenated dideoxy saccharide derivatives, preparation method and use thereof

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US (1) US9296774B2 (ko)
EP (1) EP2520580B1 (ko)
JP (1) JP5670478B2 (ko)
KR (1) KR101478758B1 (ko)
CN (1) CN102115483B (ko)
WO (1) WO2011079494A1 (ko)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2496664B1 (de) 2009-11-04 2014-10-01 Merck Patent GmbH Verbindungen für ein flüssigkristallines medium und deren verwendung für hochfrequenzbauteile
CN103120681A (zh) * 2012-10-25 2013-05-29 吴俊华 Aphanamixoid A在抗肺癌转移药物中的应用
CN103120665A (zh) * 2012-10-25 2013-05-29 吴俊华 Aphanamixoid A在治疗前列腺癌药物中的应用

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8803076D0 (en) * 1988-02-10 1988-03-09 Erba Carlo Spa 3'-deamino-4'-deoxy-4'-amino anthracyclines
US4912204A (en) * 1988-09-06 1990-03-27 Bristol-Myers Company Fluoro-substituted epipodophyllotoxin glucosides
DE3835772A1 (de) * 1988-10-20 1990-04-26 Deutsches Krebsforsch Tumorhemmende saccharid-konjugate
JPH02178298A (ja) * 1988-12-28 1990-07-11 Sumitomo Pharmaceut Co Ltd 新規アミノナフタセン誘導体
CN1025918C (zh) * 1990-06-07 1994-09-14 国家医药管理局上海医药工业研究院 抗肿瘤药表鬼臼毒吡喃糖甙的合成新工艺
JPH09132589A (ja) * 1995-09-08 1997-05-20 Microbial Chem Res Found 糖部分の水酸基をモノ−または−ジ−ｏ−アミノアルカノイル化された含フッ素アンスラサイクリン誘導体
FR2739857B1 (fr) * 1995-10-12 1998-01-02 Pf Medicament Nouveaux derives amines de 2",3"-didesoxyglycosides d'epipodophyllotoxine, leur procede de preparation, leur utilisation comme medicament et leur utilisation destinee aux traitements anticancereux
BRPI0406667A (pt) * 2003-01-10 2005-12-20 Threshold Pharmaceuticals Inc Método para o tratamento de câncer, e, formulação terapeuticamente aceitável de 2-dg
CN100357305C (zh) * 2005-12-30 2007-12-26 江苏汉发贸易发展有限公司 乙酰化葡萄烯糖的制备方法
WO2008011588A2 (en) * 2006-07-20 2008-01-24 Threshold Pharmaceuticals, Inc. Glycoconjugates of phosphoramidate alkylators for treatment of cancer
CN101481394B (zh) * 2008-01-09 2013-01-30 苏州天人合生物技术有限公司 2,3,4,6-四-o-乙酰基-d-吡喃葡萄糖基-[n, n′-双(2-氯乙基)]-磷酸二酰胺的制备方法
WO2009143515A2 (en) * 2008-05-23 2009-11-26 University Of Miami Treatment using continuous low dose application of sugar analogs

Also Published As

Publication number Publication date
EP2520580A1 (en) 2012-11-07
JP5670478B2 (ja) 2015-02-18
KR101478758B1 (ko) 2015-01-02
US9296774B2 (en) 2016-03-29
JP2013515750A (ja) 2013-05-09
CN102115483B (zh) 2014-12-17
EP2520580A4 (en) 2013-09-04
WO2011079494A1 (zh) 2011-07-07
CN102115483A (zh) 2011-07-06
US20120283198A1 (en) 2012-11-08
KR20120084772A (ko) 2012-07-30

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